Fas receptor (CD95, TNFR6) is a member of the TNF receptor superfamily and is best characterized for its ability to induce extrinsic apoptosis upon ligation of its ligand, FasL. Following Fas activation, Fas-associated protein with death domain (FADD) and caspase-8 are recruited to the receptor to form the death-inducing signalling complex (DISC). Fas-FasL interactions are crucial in the maintenance of immune homeostasis; in particular by mediating paracrine apoptosis of CD8+ cytotoxic-T cells to down-regulate immune responses.
Recent work in our laboratory showed that the intestinal pathogen, Enteropathogenic E. coli (EPEC) secretes an effector protein, NleB, that targets FADD and ablates FasL mediated caspase-8 activation in epithelial cells (see poster by Jaclyn Pearson). Fas is expressed on the basolateral surface of intestinal epithelial cells, however the purpose of Fas-FasL interactions (homeostatic or immune regulatory) in this cell type is not clear. Infection of C57BL/6 mice with the model organism Citrobacter rodentium, deficient in nleB, shows impaired colonization compared to wild-type C. rodentium, indicating that the inhibition of Fas signalling in the intestinal epithelium is critical for the bacteria to establish fulminant disease. Conversely, infection of Fas-lpr mice, which do not express Fas receptor, with the nleB-deficient C. rodentium rescues the colonization defect, highlighting the importance of Fas-signalling in controlling C. rodentium infection. Interestingly, infection of Fas-lpr mice with wild-type C. rodentium leads to increased inflammation in the colonic mucosa, increased mucosal bacterial invasion and higher diarrhea scores compared to symptoms observed in C57BL/6 mice.
This study aims to interrogate the role of Fas signalling in controlling mucosal infections. In particular, we aim to clarify the key cell types which express Fas and FasL and how they interact together to control C. rodentium infection.